Weight loss and depletion of body tissues occur frequently in patients with cancer and are usually associated with a poor outcome. For many patients decreased food intake alone cannot account for the severity of the observed weight loss and it is likely that metabolic abnormalities contribute to this condition. This study proposes to test the hypothesis that weight loss in patients with cancer is in part due to an increase in total daily energy expenditure as a result of inefficient utilization of absorbed nutrients due to substrate cycling. Substrate cycles occur when two opposing metabolic reactions, catalyzed by different enzymes, proceed simultaneously causing an increase in heat production and energy expenditure without any increase in the net flux of metabolites. The proposed project will assess changes in body composition, diet-induced thermogenesis, total energy expenditure, whole-body protein kinetics (turnover, synthesis, and catabolism), and plasma protein (total proteins, albumin, fibrinogen, and fibronectin) synthetic rates during 8 days of normal and 8 days of high calorie dietary intake. In addition, glucose, glycerol, and palmitate flux and substrate (glucose to glucose-6-phosphate to glucose, triglyceride to fatty acid to triglyceride) cycling will be assessed in the basal state and in response to nutrient (euglycemic-insulin clamp) infusion. Stable, nonradioactive tracers will be used to measure these parameters. Four groups of subjects will be studied: (1) patients with oropharyngeal cancer who have lost 10-20% body weight in the past 6 mo, (2) patients with oropharyngeal cancer who have lost less 5% body weight in the past 6 mo, (3) patients without cancer or inflammatory disease who have lost 10-20% body weight in the past 6 mo, and (4) volunteers of normal weight. The selection of these groups will aid in distinguishing metabolic abnormalities due to the presence of tumor from those due to malnutrition, weight loss, or differences in body composition. Patients with oropharyngeal cancer have been particularly chosen for study because of previous evidence demonstrating that these patients have difficulty gaining weight despite dramatic increases in calorie intake. Clinical trials in cancer patients thus far have not demonstrated a significant improvement in clinical outcome when standard nutritional support is provided. This proposal will provide a better understanding of the metabolic abnormalities that contribute to cancer cachexia and may be important in developing new therapeutic strategies for the nutritional management of cancer patients.